Abstract This Asthma and Allergic Disease Cooperative Research Center (AADCRC) continues its focus on the mechanistic basis of aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of individuals with severe asthma and recurrent nasal polyps. AERD is associated with aberrant/persistent mast cell (MC) activation and generation of the cysteinyl leukotrienes (cysLTs). Both features are markedly further induced during pathognomonic clinical reactions aspirin or other nonselective inhibitors of cyclooxygenase (COX), reflecting impairements in the homeostatic prostaglandin (PG)E2 synthetic system. In the current period of support, we discovered critical roles for platelets and T prostanoid (TP) receptors in AERD pathogenesis, and uncovered a strong contribution from MC-derived PGD2 and thromboxane (TX)A2 in driving the persistent respiratory inflammation associated with the disease. We now find remarkably increased expressions of cytokines derived from activated structural cells (interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP)) in the nasal tissue of subjects with AERD compared to AT controls. Additionally, we found that cysLTs act in vivo at (a) montelukast-resistant receptor(s) to drive IL-33 overproduction, that MC activation in AERD occurs by a unique IL-33-driven mechanism, and that IL-33 and TSLP elicit MC-derived PGs as effectors to amplify type 2 inflammation. A team of highly accomplished investigators with complementary skills will apply cellular, molecular, and whole animal strategies, combined with a proof-of-concept clincal trial to determine the mechanistic basis for these findings, their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the mechanisms and by which IL-33, TSLP, and PGE2 alter MC function in nasal polyps, and the physiolgic consequences. Project 2 (N. Barrett, PI) will determine the cell types and cysLT receptors that drive lung IL-33 in murine AERD, and will define the contributions of IL-33 and PGE2 in determinng the transcriptional profile of mouse and human MCs in the AERD milieu. Project 3 (E. Israel, PI) will determine the efficacy of TP receptor blockade on the severity of clinical reactions to aspirin, and will determine whether TP blockade interrupts a pathogenic feed-forward loop. The Projects are supported by respective Cores for Adminstration (Core A), Genomics/Informatics/Statistics (Core B), and Sample Biorepository and Analysis (Core C).